Abstract Dementia with Lewy Bodies (DLB) is an alpha-synucleinopathy and the second most common form of dementia in the elderly. DLB shares striking neuropathological and clinical similarities with both Parkinson's disease (PD) and Alzheimer's disease (AD). Nilotinib (Tasigna, AMN107, Novartis, Switzerland) is approved by the FDA and is well tolerated for CML treatment at oral doses of 600-800mg daily. We previously showed that lower doses of Nilotinib penetrates the brain and facilitates autophagic degradation of neurotoxic proteins, promotes survival of dopamine (DA) and other neurons and improve motor and cognitive behavior in animal models of alpha-synucleinopathy and other neurodegenerative diseases. Based on these strong pre-clinical evidence of the effects of Nilotinib on neurodegenerative pathologies, we conducted an open label pilot clinical trial in individuals with mid-advanced PD with dementia (PDD) and DLB to study the safety of Nilotinib in this population. Participants (N=12) were randomized 1:1 to once daily oral dose of 150mg and 300mg Nilotinib for 6 months. Our data suggest that Nilotinib penetrates the brain and inhibits cerebrospinal fluid (CSF) tyrosine kinase Abelson (Abl) activity in agreement with pre-clinical data. Several studies show that CSF alpha- synuclein, Abeta42, total tau and p-tau181 are altered in PD and DLB. Our data show stabilization of total CSF alpha-synuclein but a reduction in oligomeric:total alpha-synuclein ratio between baseline and 6-months treatment with 150mg-300mg Nilotinib. CSF homovanillic acid (HVA), which is an end by-product of DA, was also significantly increased; and CSF total tau and p-tau were significantly reduced (N=5, P<0.05) with 300mg Nilotinib between baseline and 6-month treatment. L-Dopa replacement therapies (including MOAB inhibitors) were reduced at 2 months in this study, but the Unified Parkinson?s Disease Rating Scale (UPDRS) I-IV improved with 150mg (3.5 points) and 300mg (11 points) from baseline to 6 months and worsened (13.7 points and 11.4 points) after 3-month withdrawal of 150mg and 300mg, respectively. Cognition was also improved (3.5 points) using both the Mini-Mental Status Exam (MMSE) between baseline and 6 months. MMSE scores returned to baseline after 3 months of Nilotinib withdrawal. It is important to note that participants who received oral daily dose of 150mg Nilotinib in this phase I open label study were all individuals with DLB. We conducted further phase II dose-finding random multiple dose studies that included placebo, 100mg, 200mg, 300mg and 400mg administered orally once 1-4 hours prior to lumbar puncture (LP) in PD patients who were not on MOAB inhibitors for at least 6 weeks prior to dosing. We observed that 200mg oral dose of Nilotinib results in a significant increase in CSF HVA and 3.4-didydroxyphenylacetic acid (DOPAC) concurrent with a decrease in CSF oligomeric alpha-synuclein (Interim analysis NCT02954978). Taken together, data from our two studies indicate that 200mg Nilotinib may be an optimal dose to study in DLB patients. Our data are very compelling to evaluate the effects of 200mg Nilotinib in a phase II, randomized, double-blinded, placebo-controlled trial in patients with DLB.